Suicide has a biological as well as a psychosocial basis. We have confirmed evidence of altered serotonergic and noradrenergic activity that may be interpreted as decreased serotonergic and increased noradrenergic activity in the prefrontal cortex of suicide victims: We found: (1) increased 125-I-iodolysergic acid diethylamide (125-I-LSD) binding; (2) localized increases in 5-HT-1A and serotonin transporter binding to Brodmann's area 46 on the medial frontal gyrus; (3) no alteration in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in areas 9 (prefrontal) and 38 (temporal); (4) high affinity beta-adrenergic receptors are increased (5) alpha1- but not alpha2-adrenergic binding appeared to be increased; (6) norepinephrine (NE) levels are higher in cortical areas 9 and 38. Our current proposal aims to determine: (1) whether alterations in the serotonergic system in violent suicide victims are localized to specific brain regions beyond the prefrontal cortex; (2) the biochemical specificity of alterations in the serotonergic system by mapping pre- and postsynaptic serotonergic changes; (3) determine if changes in gene expression correlate with altered receptor number in specific brain regions of suicide victims; (4) establish the regional and biochemical specificity of the noradrenergic system defects; (5) distinguish specific neurochemical correlates of suicide vs. a depressive illness; (6) complete the computerized brain image data set on the serotonergic and noradrenergic systems in the prefrontal cortex and extend it to midcallosal and splenial levels as a resource for future brain studies. These studies combine receptor binding and gene expression assays in adjacent slices from full coronal sections of human brain to verify our current findings in the prefrontal cortex and examine additional brain regions to define in detail the extent and specificity of the serotonergic changes in suicidal behavior in terms of brain region and compared to the noradrenergic system. Evidence that a highly localized and biochemically specific alteration within the serotonergic and noradrenergic systems may underlie suicidal behavior, independent of Major Depression, has profound consequences for conceptualizing the basis of suicidal behavior as well as the development of effective, specific pharmacotherapy of suicide, the cause of death of 32,000 people per year in the United States.